A comparison was made of the protective effects of amifostine (WR2721) and dexrazoxane (ICRF-187) against the chronic toxicity induced by doxorubicin in spontaneously hypertensive rats (SHR). To achieve this the animals were pretreated with amifostine (200 mg/kg, i.p.), dexrazoxane (25 mg/kg, i.p.) or saline 30 min before the administration of doxorubicin (1 mg/kg, i.v.), once weekly for 12 weeks. Control animals received similar amounts of amifostine or saline. The SHR underwent necropsy examination one week after the last dosing, and cardiac, renal, and gastrointestinal lesions were graded semiquantitatively. Amifostine and dexrazoxane provided equal degrees of protection against the renal toxicity of doxorubicin. However, dexrazoxane was more cardioprotective than amifostine, and prevented the mortality induced by doxorubicin. This mortality was not decreased by pretreatment with amifostine. The loss of body weight caused by doxorubicin was actually worsened by coadministration of amifostine. Compared to dexrazoxane, amifostine provided a comparable degree of protection against the nephrotoxicity of doxorubicin, but was less cardioprotective and did not prevent the mortality and loss of body weight produced by the latter agent. These differences may be related to the fact that amifostine may act as a scavenger of reactive oxygen species, whereas dexrazoxane may prevent their formation. - doxorubicin, cardiac toxicity, Dexrazoxane (ICRF-187), iron chelation